The present invention relates to a method for producing a polyalkylene glycol derivative, with narrow molecular weight distribution, having an amino group at an end, and a new acetal group-containing alcohol compound for use therein and an alkali metal salt thereof.
Recently, in drug delivery systems, a method for encapsulating drugs in a polymer micelle using a block copolymer formed from a hydrophilic segment and a hydrophobic segment has been proposed (refer to, for example, Japanese Patent No. 2690276, Japanese Patent No. 2777530, and Japanese Patent Application Laid-Open No. 11-335267). By using this method, the polymer micelle functions as a carrier for drugs, producing various effects including sustained release in vivo and concentrated dosage at an affected region.
As the hydrophilic segment, many examples with use of a polyalkylene glycol skeleton have been proposed (refer to, for example, Japanese Patent No. 2690276, Japanese Patent No. 2777530, and Japanese Patent Application Laid-Open No. 11-335267). A compound having a polyalkylene glycol skeleton has low toxicity in vivo, and enables excretion by the kidney to be delayed. Consequently, in comparison with a compound having no polyalkylene glycol skeleton, the retention time in blood can be prolonged. As a result, with the use of a drug that is contained in a micelle of a polyalkylene glycol derivative, the dosage amount or dosage frequency can be reduced.
Among polyalkylene glycol derivatives, a compound having an amino group at an end can lead to a block copolymer composed of a polyalkylene glycol skeleton and an amino acid skeleton through a ring-opening polymerization reaction with α-amino acid-N-carboxyanhydride. Many examples with use of the produced block copolymer for encapsulating drugs in a polymer micelle have been proposed (refer to, for example, Japanese Patent No. 2690276, Japanese Patent No. 2777530, and Japanese Patent Application Laid-Open No. 11-335267).
Synthesis methods of such polyalkylene glycol derivatives having an amino group at an end are also known (refer to, for example, Japanese Patent No. 3050228 and Japanese Patent No. 3562000). In these methods, after polymerization of alkylene oxide with use of a metal salt of monohydric alcohol as a polymerization initiator, a polymer end is converted to a hydroxyl group, and then to a 2-cyanoethoxy group, finally leading to an amino group-containing substituent group (3-amino-1-propoxy group) through hydrogen reduction of the cyano group.
As a synthesis method of polyalkylene glycol derivatives having an amino group, a synthesis example by a reductive amination reaction is also reported. In the method, after polymerization of ethylene oxide with use of a potassium salt of 3,3-diethoxypropanol, the acetal end of the produced polymer is converted to a formyl group. Further, the polymer end leads to an amino group through a reductive amination reaction (refer to, for example, International Publication WO 2008/71009).
In regard to polyalkylene glycol having a formyl group at an end, many synthesis examples with use of an alkali metal salt of 3,3-diethoxypropanol are reported in the literature other than described above (refer to, for example, Bioconj. Chem. 1995, 6(2), 231-233 and International Publication WO 2010/55866). In these methods, however, the polymerization reaction requires a time for completion of 1 day or more, under conditions of high temperature and high pressure.